Cyclophosphamide is a synthetic antineoplastic drug which is chemically related to the nitrogen mustards. Cyclophosphamide, having the chemical name 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide, can exist in both monohydrate and anhydrous forms as shown in Formula I and Formula II below:

The monohydrate form is preferred for pharmaceutical processing, as the anhydrous form was reported to be highly unstable and readily picks up water to form the monohydrate when exposed to a relative humidity of about 20-30% or higher at about 25° C. The monohydrate drug form is stable but, under dry conditions (relative humidity of about 20% or less), begins to lose the water of hydration, giving rise to unwanted degradation products which may potentially impact product quality and end-use limitation. Accordingly, maintaining proper manufacturing and storage conditions are essential to product quality attributes and critical for application for approved regulatory usage.
Cyclophosphamide is available in sterile parenteral dosage formulations consisting of sterile packaged dry powder blend admixtures of cyclophosphamide monohydrate and sodium chloride, which are dissolved in water prior to administration. However, such formulations have disadvantages, such as glassiness and/or stickiness acquired by the powder premix composition during the processing and storage, which might impact overall product quality and end-use applicability, including inferior solubility and decreased potency, as well as deterioration during storage.
Lyophilization, or freeze drying, is a process for creating or isolating a stable preparation of a solid product by freezing and dehydration and/or removal of solvents utilized for dissolution of the frozen product under vacuum. The sublimation of the ice from the frozen solution leaves the solid, dried components of the original liquid.
U.S. Pat. No. 4,537,883 to Alexander et al. discloses that a lyophilized cyclophosphamide solid composition containing 4% moisture gave a product with superior thermal stability, compared to lyophilized cyclophosphamide solid compositions with moisture levels of 1% or less, or even cyclophosphamide itself. It describes two methods to prepare the solid compositions. One method involves lyophilization of a sterile solution of cyclophosphamide, mannitol and water in a short period of time (24 hours) to produce a “dry” lyophilizate having a moisture content of 2% or less, then humidifying the “dry” lyophilizate to give a “hydrated” lyophilizate containing approximately 4% moisture. The other method involves lyophilization of the sterile solution using a longer 2 stage lyophilization process (48 hours), where the first stage of freeze-drying was done with a low condenser temperature of −60° C. and a shelf temperature at 10° C., and when the product temperature (measured by thermocouple) reached about −12° C., the second stage of freeze-drying was conducted by raising the condenser temperature to −30° C. and lowering the shelf temperature to −10° C.
U.S. Pat. No. 4,659,699 to Daniel et al. discloses a two-stage process involving freeze drying an aqueous solution of cyclophosphamide with an excipient until the moisture content is less than 2% by weight, then rehydrating the freeze dried material to the moisture content in the critical range of 2-7% by weight.
U. S. Patent Application Publication No. 2015/0290226 of Chandrashekhar et al. describes a lyophilization process that did not need rehydration step and produced crystalline monohydrate form containing 5.7 to 6.8% of water. The lyophilization was conducted with one or more organic solvents or a mixture of organic solvent(s) and water.
Many known lyophilized preparations of cyclophosphamides or similar drugs contain components such as bulking or matrix forming agents. These additives include salts such as sodium chloride, mono-, di- and polysaccharides, and sugar alcohols such as mannitol. D-mannitol is known to exist as three polymorphs: α (also known as κ), β, and δ. Preparations which are mannitol free are also known. For example, U.S. Pat. No. 5,036,060 of Alam et al. describes a mannitol-free lyophilized formulation of cyclophosphamide. The formulation is prepared from a solution of cyclophosphamide, water, and sodium chloride, and involves performing several freezing and cooling steps, applying vacuum, and drying until a target moisture content is achieved.
Many prior art processes require a rehydration step at the end of processing, and others require the use of solvents other than water. These processes are disadvantageous for several reasons. For examples, a rehydration step may result in significant variability in the moisture level from vial to vial within a single batch, as well as variability from batch to batch. The use of solvents other than water introduces additional residual materials that must be quantified and controlled.
There is a need for improved lyophilized cyclophosphamide compositions and improved methods for lyophilizing cyclophosphamide.